The DNA Damage and Cellular Defense Program consists of 19 members of the Comprehensive Cancer Center of Wake Forest University, representing 6 Departments. The overall scientific goal within the DNA Damage and Cellular Defense Program is to understand the mechanisms and processes whereby cells sustain-or alternatively, mitigate by prevention or repair-damage to DNA or other critical macromolecular structures. The Specific Aims of this Program are: 1) To determine mechanisms of damage to DNA by redox-active or electrophilic chemical agents implicated in carcinogenesis. The focus of research in Aim #1 may be divided into two subgroups. One is concerned with mechanisms of DNA damage by redox-active or free radical species, enhancement by metal ions of oxidative damage to DNA, and the role of metal ions in determining the resulting base or sequence specificity of oxidative damage. A second subgroup is interested in electrophilic agents that form cytotoxic and/or mutagenic DNA adducts, often after metabolic activation by phase 1 enzymes such as the cytochrome P450 mixed- function oxidases. 2) To identify and define the significance of phenotype or genotypic factors that determine relative susceptibility to DNA- damaging agents among different cell/tissue types and between organisms. One focus on the mechanisms and relative contribution of specific enzymatic pathways to cellular defenses against DNA damage by electrophiles and reactive oxygen species. A second focus is on cellular regulatory pathways and genetic differences that govern cellular sensitivity to DNA damaging agents. The DDCD Program has a strong funding and productivity record. Total funding of $1.8 M includes 47% NCI funding, and a 88% increase in NCI funding over the past three years. Membership has been reorganized and more narrowly limited to cancer focused investigators; four new faculty recruits have been added since 1997. Members rely heavily on core lab services in support of their research, and have made efficient use of pilot funding mechanisms, many of which have matured into funded grants. Members are highly interactive, with 21 intraprogrammatic publications out of 140 listed since 1996. There are 8 established interactions, and 12 new collaborations begun in the past two years. A number of new and established translational projects a ongoing, with several more pending review.